Some porphyrins and related tetrapyrrolic compounds, e.g. chlorins and bacteriochlorins, tend to be retained in malignant tumors in higher concentrations than in normal tissues. When the tetrapyrrolic compound is exposed to light of an appropriate wavelength, an excited state may occur and a singlet oxygen atom may be released. Such compounds which become excited by light are referred to herein as photodynamic compounds. When a patient is injected with an appropriate dose of a photodynamic compound, as previously described, the compound will concentrate in tumors which are present. The tumor may then be exposed to the appropriate wavelength of light to activate the compound which results in a tumoricidal effect. The release of singlet oxygen may be the cytotoxic species which, along with various other oxygen containing radicals, kills the tumor.
Porphyrins, chlorins, and bacteriochlorins including their analogs and derivatives have therefore recently found superior utility as photodynamic compounds for use in diagnosis and treatment of disease, especially certain cancers. These compounds have also found utility in treatment of psoriasis and papillomatosis.
Photofrin.RTM. (a porphyrin derivative), has been studied in most detail and is currently being used all over the world for treatment of various types of cancers. Despite the fact that it has already been approved for commercialization in Canada, Japan, and the United States, Photofrin photosensitizing agent has some disadvantages. In particular, it both photosensitizes the skin and lacks rapid normal tissue clearance, so patients must avoid exposure to sunlight for an extended period after its use. Further, it is a complex mixture of ether and ester linked dimers and higher oligomers, making it difficult to study mechanistically.
Photofrin photosensitizing agent also absorbs at a short wavelength making deep tissue penetration difficult and sometimes not possible. It is well established that both absorption and scattering of light by tissue increases as the wavelength decreases, and the most efficient photosensitizers are those which have strong absorption bands at the red end of the visible spectrum and the near IR region. Heme proteins accounts for most of the absorption of light in the visible region. Since this drops off rapidly beyond 550 nm, the effective depth of penetration doubles from 550 to 630 nm (where Photofrin.RTM. is activated) and doubles again in going to 700 nm, followed by 10% increase in penetration by moving into the near IR region (800 nm). However, further red shift is neither desirable (because of the lack of benefit from deeper penetration) nor easily achievable. Another reason to set the ideal wavelength in the range of 700-800 nm is due to the availability of diode lasers. Advantages of diode lasers are the low cost, negligible running cost, high reliability, small size and portability. Besides these considerations, tumor localization, dark toxicity, phototoxicity, stability and formulation are also among the basic criteria to be considered for developing an efficient photosensitizer.
There is therefore still a quest for additional and new compounds for use in the field which have lower phototoxicity, better tissue clearance, better effectiveness and which absorb at higher wave lengths for better penetration.